The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, and activation of B lymphocytes. The BCR is composed of membrane immunoglobulin (IgM) molecules associated with CD79a molecule, immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated beta heterodimers (CD79 complex) [1]. The IgM subunits bind antigens and cause receptor aggregation, while the CD79 complex subunits transduce intracellular signaling cascades. Upon activation, BCRs activate the Spleen tyrosine kinase (Syk) and v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn), which phosphorylate and activate Phospholipases C, gamma (PLC-gamma), and Bruton agammaglobulinemia tyrosine kinase (BTK), respectively. BTK also activates both PLC-gamma isoforms [2], [3].

Once activated, these tyrosine kinases phosphorylate activate several signaling pathways, including Ras-ERK and PLC-gamma signal cascades, which lead to the activation of transcription factors, such as ELK1, member of ETS oncogene family (ELK1), Early growth response 1 (EGR1), Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NF-AT1(NFATC2)) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB), and inhibit transcription factors, such as B-cell CLL/lymphoma 6 (Bcl-6).

PLC-gamma activation that is mediated by BTK and B-cell linker (BLNK), leads to the conversion of phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2) to the second messengers inositol-1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). IP3 binds to Inositol 1,4,5-triphosphate receptor (IP3 Receptor), which is localized primarily on the endoplasmic reticulum and stimulates the release of calcium from intracellular stores. Calcium-bound Calmodulin 2 (Calmodulin) associates with and activates Protein phosphatase 3, catalytic subunit (Calcineurin A (catalytic)). Calcineurin A (catalytic) dephosphorylates NF-AT1(NFATC2) leading to theirs translocation to the nucleus [4].

DAG activates Protein kinase C, beta (PKC-beta). PKC-beta in particular, is a critical component of the BCR signalosome, and is essential for recruitment and activation of the IKK complex resulting in the translocation of NF-kB to the nucleus [5].

Several transmembrane receptors are known to modulate specific elements of BCR signaling. These include Protein tyrosine phosphatase, receptor type, C (CD45) and Fc fragment of IgG, low affinity IIb, receptor (Fc gamma RII beta).CD45 has its own protein tyrosine phosphatase activity and inhibits v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn) activity by dephosphorylation leading to reduction in CD45's negative regulatory effects [6], [7].

Lyn phosphorylates and activates co-receptor CD19 molecule (CD19) and receptor Fc-gamma-RII [8], [9]. CD19 is a cell surface molecule, which assembles with the antigen receptor of B lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation. This co-receptor complex is composed of CD19, Complement component receptor 2 (CD21) and CD81 molecule (CD81) [10]. CD21 binds to opsinized antigenic particles and is primarily responsible for signal transduction. Phosphorylation of CD19 by Lyn generates binding sites for Phosphoinositide-3-kinase, catalytic (PI3K cat class IA). PI3K cat class IA activates Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) and Vav 1 and 2 guanine nucleotide exchange factors (VAV-1 and VAV-2). The CD19 co-receptor physically interacts with VAV-1 and VAV-2 and synergistically enhances their phosphorylation induced by the BCR. VAV-1 and VAV-2 activate small GTP binding proteins Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (CDC42) [11].

PtdIns(3,4,5)P3 associates with the inner phospholipid bilayer of the plasma membrane to promote the recruitment of pleckstrin homology (PH) domain-rich proteins such as 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) and V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)). PDK (PDPK1) activates AKT(PKB), which phosphorylates downstream target including BCL2 Antagonist of Cell Death (BAD), Glycogen synthase kinase 3 beta (GSK3 beta) and Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (P70 S6 kinase1), thereby regulating apoptosis, cell cycle, cell growth and other cellular processes [12].

Fc-gamma-RII activates the Inositol polyphosphate-5-phosphatase, 145kDa (SHIP). SHIP converts PtdIns(3,4,5)P3 into PtdIns (3,4)P2, which is the second messenger that activates PDK (PDPK1) and AKT(PKB) [13].

Lyn also participates in the negative regulation of BCR signaling. Lyn phosphorylates CD22 molecule (CD22), which binds to the Protein tyrosine phosphatase, non-receptor type 6 (SHP-1) and induces Lyn dephosphorylation by SHP-1, thereby down-regulating Btk-dependent IP3 production and calcium mobilization [14], [15].

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